Abstract
Bone regeneration is a complex, well-orchestrated physiological process of bone formation, which can be seen during normal fracture healing, and is involved in continuous remodelling throughout adult life. However, there are complex clinical conditions in which bone regeneration is required in large quantity, such as for skeletal reconstruction of large bone defects created by trauma, infection, tumour resection and skeletal abnormalities, or cases in which the regenerative process is compromised, including avascular necrosis, atrophic non-unions and osteoporosis. Currently, there is a plethora of different strategies to augment the impaired or ‘insufficient’ bone-regeneration process, including the ‘gold standard’ autologous bone graft, free fibula vascularised graft, allograft implantation, and use of growth factors, osteoconductive scaffolds, osteoprogenitor cells and distraction osteogenesis. Improved ‘local’ strategies in terms of tissue engineering and gene therapy, or even ‘systemic’ enhancement of bone repair, are under intense investigation, in an effort to overcome the limitations of the current methods, to produce bone-graft substitutes with biomechanical properties that are as identical to normal bone as possible, to accelerate the overall regeneration process, or even to address systemic conditions, such as skeletal disorders and osteoporosis.
Introduction
Bone possesses the intrinsic capacity for regeneration as part of the repair process in response to injury, as well as during skeletal development or continuous remodelling throughout adult life1,2. Bone regeneration is comprised of a well-orchestrated series of biological events of bone induction and conduction, involving a number of cell types and intracellular and extracellular molecular-signalling pathways, with a definable temporal and spatial sequence, in an effort to optimise skeletal repair and restore skeletal function2,3. In the clinical setting, the most common form of bone regeneration is fracture healing, during which the pathway of normal fetal skeletogenesis, including intramembranous and endochondral ossification, is recapitulated4. Unlike in other tissues, the majority of bony injuries (fractures) heal without the formation of scar tissue, and bone is regenerated with its pre-existing properties largely restored, and with the newly formed bone being eventually indistinguishable from the adjacent uninjured bone2. However, there are cases of fracture healing in which bone regeneration is impaired, with, for example, up to 13% of fractures occurring in the tibia being associated with delayed union or fracture non-union5. In addition, there are other conditions in orthopaedic surgery and in oral and maxillofacial surgery in which bone regeneration is required in large quantity (beyond the normal potential for self-healing), such as for skeletal reconstruction of large bone defects created by trauma, infection, tumour resection and skeletal abnormalities, or cases in which the regenerative process is compromised, including avascular necrosis and osteoporosis.
Current clinical approaches to enhance bone regeneration
For all the aforementioned cases in which the normal process of bone regeneration is either impaired or simply insufficient, there are currently a number of treatment methods available in the surgeon’s armamentarium, which can be used either alone or in combination for the enhancement or management of these complex clinical situations, which can often be recalcitrant to treatment, representing a medical and socioeconomic challenge. Standard approaches widely used in clinical practice to stimulate or augment bone regeneration include distraction osteogenesis and bone transport6,7, and the use of a number of different bone-grafting methods, such as autologous bone grafts, allografts, and bone-graft substitutes or growth factors8,9. An alternative method for bone regeneration and reconstruction of long-bone defects is a two-stage procedure, known as the Masquelet technique. It is based on the concept of a “biological” membrane, which is induced after application of a cement spacer at the first stage and acts as a ‘chamber’ for the insertion of non-vascularised autograft at the second stage10. There are even non-invasive methods of biophysical stimulation, such as low-intensity pulsed ultrasound (LIPUS) and pulsed electromagnetic fields (PEMF)11-13, which are used as adjuncts to enhance bone regeneration.
During distraction osteogenesis and bone transport, bone regeneration is induced between the gradually distracted osseous surfaces. A variety of methods are currently used to treat bone loss or limb-length discrepancies and deformities, including external fixators and the Ilizarov technique6,7, combined unreamed intramedullary nails with external monorail distraction devices14, or intramedullary lengthening devices15. However, these methods are technically demanding and have several disadvantages, including associated complications, requirement for lengthy treatment for both the distraction (1 mm per day) and the consolidation period (usually twice the distraction phase), and effects on the patient’s psychology and well-being6,7.
Bone grafting is a commonly performed surgical procedure to augment bone regeneration in a variety of orthopaedic and maxillofacial procedures, with autologous bone being considered as the ‘gold standard’ bone-grafting material, as it combines all properties required in a bone-graft material: osteoinduction (bone morphogenetic proteins (BMPs) and other growth factors), osteogenesis (osteoprogenitor cells) and osteoconduction (scaffold)16. It can also be harvested as a tricortical graft for structural support16, or as a vascularised bone